A5022397913- Malaria Research and Control
- Chemical Synthesis and Analysis
- HIV Research and Treatment
- Monoclonal and Polyclonal Antibodies Research
- Complement system in diseases
- Bacteriophages and microbial interactions
- Peptidase Inhibition and Analysis
- Mosquito-borne diseases and control
- Invertebrate Immune Response Mechanisms
- Mass Spectrometry Techniques and Applications
- Trypanosoma species research and implications
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Neuropeptides and Animal Physiology
- Computational Drug Discovery Methods
- Virus-based gene therapy research
- SARS-CoV-2 and COVID-19 Research
- Analytical Chemistry and Chromatography
- Influenza Virus Research Studies
- vaccines and immunoinformatics approaches
- Antifungal resistance and susceptibility
- interferon and immune responses
- Cell Adhesion Molecules Research
- Pharmacological Effects and Assays
- Respiratory viral infections research
University of Oxford
2022-2024
University of Illinois Urbana-Champaign
2024
Scripps Research Institute
2019-2023
La Jolla Alcohol Research
2022
Bowdoin College
2017
Abstract The most advanced P. falciparum circumsporozoite protein-based malaria vaccine, RTS,S/AS01 (RTS,S), confers partial protection but with antibody titers that wane relatively rapidly, highlighting the need to elicit more potent and durable responses. Here, we elucidate crystal structures, binding affinities kinetics, in vivo of eight anti-NANP antibodies derived from an RTS,S phase 2a trial encoded by three different heavy-chain germline genes. structures reinforce importance...
The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen Pf sporozoites, is paramount development an effective malaria vaccine. Here we present in-depth structural and functional analysis a panel potent antibodies encoded by immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which among most prevalent families induced in anti-PfCSP immune response targets Asn-Ala-Asn-Pro (NANP) repeat region....
A functional human IgA response to malaria targets a conserved epitope in the N terminus of Plasmodium falciparum circumsporozoite protein.
Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, to date, only that has demonstrated significant reduction clinical severe in endemic cohorts Phase 3 trials. Although protective, efficacy declines over time with kinetics paralleling decline antibody Pf circumsporozoite protein (PfCSP). most attention focused on antibodies repeat motifs PfCSP, other regions may play a role protection. Here, we expressed...
The conserved stem domain of influenza hemagglutinin (HA), which is classified into group 1 and 2, a target broadly neutralizing antibodies. While many HA antibodies have been described, much less known about 2 This study structurally characterizes two antibodies, 2F02 AG2-G02, targeting the central epitope lower epitope, respectively. Unlike prototypic AG2-G02 do not compete for binding. Both offer protection in vivo despite having minimal neutralization activity vitro. We further...
Seasonal influenza viruses cause significant global illness and death annually, the potential spillover of avian H5N1 poses a serious pandemic threat. Traditional vaccines target variable hemagglutinin (HA) protein, necessitating annual vaccine updates, while slower-evolving neuraminidase (NA) presents promising for broader protection. We investigated breadth anti-NA B cell responses to seasonal vaccination in humans. screened plasmablast-derived monoclonal antibodies (mAbs) from three...
Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), an attractive target vaccine development and most protective antibodies studied to date interact with central NANP repeat region of PfCSP. However, it remains unclear what structural functional characteristics correlate better by one antibody over another. Binding junctional between N-terminal domain repeats proposed result in...
Malaria vaccine candidate RTS,S/AS01 is based on the central and C-terminal regions of circumsporozoite protein (CSP) P. falciparum. mAb397 was isolated from a volunteer in an clinical trial, it protects mice infection by malaria sporozoites. However, originates less commonly used VH3-15 germline gene compared to VH3-30/33 antibodies generally elicited RTS,S NANP repeat region CSP. The crystal structure with NPNA4 peptide shows that NPNA forms type I β-turn main recognition motif. In most...
Incessant antigenic evolution enables the persistence and spread of influenza virus in human population. As principal target immune response, hemagglutinin (HA) surface antigen on viruses continuously acquires replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, HIV-1 envelope (Env), which is even more extensively glycosylated contains under-processed oligomannose-type clusters its dense glycan shield....
Abstract The symptoms of malaria occur during the blood stage infection, when parasite replicates within human red cells. parasite, Plasmodium vivax , selectively invades reticulocytes in a process which requires an interaction between ectodomain DARC receptor and Duffy-binding protein, PvDBP. Previous studies have revealed that small helical peptide from binds to region II PvDBP (PvDBP-RII). However, it is also known sulphation tyrosine residues on affects its binding these were not...
A primary objective in malaria vaccine design is the generation of high-quality antibody responses against circumsporozoite protein parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure highly potent anti-PfCSP L9 complex with recombinant PfCSP. We found that Fab binds multivalently to minor (NPNV) repeat domain, which stabilized by unique set affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations revealed...
Malaria is a global health concern, and research efforts are ongoing to develop superior vaccine RTS,S/AS01. To guide immunogen design, we seek comprehensive understanding of the protective humoral response against Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). In contrast well-studied responses repeat region C-terminus, antibody N-terminal domain PfCSP (N-CSP) remains obscure. Here, characterized molecular recognition functional efficacy N-CSP–specific monoclonal 5D5. The...
The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths the US over last 20 years. Though naloxone, a short-acting medication, remains primary treatment option for temporarily reversing effects, alternative countermeasures are needed. Monoclonal antibodies present versatile therapeutic opportunity that can be tailored to and help prevent post-treatment renarcotization. ultrapotent analog carfentanil is especially concerning due its unique...
The morphological transition of the opportunistic fungal pathogen Candida albicans from budding to hyphal growth has been implicated in its ability cause disease animal models. Absence SR-like RNA-binding protein Slr1 slows formation and decreases virulence a systemic candidiasis model, suggesting role for post-transcriptional regulation these processes. SR (serine-arginine)-rich proteins influence multiple steps mRNA metabolism their localization function are frequently controlled by...
Summary The generation of high-quality antibody responses to PfCSP, the primary surface antigen Plasmodium falciparum sporozoites, is paramount development an effective malaria vaccine. Here we present in-depth structural and functional analysis a panel potent antibodies encoded by IGHV3-33 germline gene, which among most prevalent families induced in anti-CSP immune response targets NANP repeat region. Cryo-EM reveals remarkable spectrum helical Fab-CSP structures stabilized homotypic...
Antibody discovery is crucial for developing therapeutics and vaccines as well understanding adaptive immunity. However, the lack of approaches to synthesize antibodies with defined sequences in a high-throughput manner represents major bottleneck antibody discovery. Here, we presented oPool + display, cell-free platform that combined oligo pool synthesis mRNA display rapidly construct characterize many natively paired parallel. As proof-of-concept, applied probe binding specificity >300...
Abstract Plasmodium vivax remains one of the major causative agents human malaria and a vaccine is urgently required. It an obligate intracellular parasites replication within red blood cells essential for development disease transmission. The interaction between PvDBP on parasite surface DARC receptor reticulocytes stage infection. Human vaccination with RII region slowed replication, showing that promising candidate. However, it did not induce sterile protection, further required to...
Despite the increased availability of serological data, understanding serodynamics remains challenging. Serocatalytic models, which describe rate seroconversion (gain antibodies) and seroreversion (loss within a population, have traditionally been fit to cross-sectional data capture long-term transmission dynamics. However, key limitation is their binary assumption on status, ignoring heterogeneity in optical density levels, antibody titers, and/or exposure history. Here, we implemented...
The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths the US over last 20 years. Though naloxone, a short acting medication, remains primary treatment option for temporarily reversing effects, alternative countermeasures are needed. Monoclonal antibodies present versatile therapeutic opportunity that can be tailored and help prevent post-treatment renarcotization. ultrapotent analog carfentanil, is especially concerning due to its unique...
Abstract The most advanced P. falciparum circumsporozoite protein (PfCSP)-based malaria vaccine, RTS,S/AS01 (RTS,S), confers partial protection but with antibody titers that wane relatively rapidly, highlighting the need to elicit more potent and durable responses. Here, we elucidate crystal structures, binding affinities kinetics, in vivo of eight anti-NANP antibodies (Abs) derived from an RTS,S phase 2a trial encoded by three different heavy-chain germline genes. structures reinforce...
Abstract A primary objective in malaria vaccine design is the generation of high-quality antibody responses against circumsporozoite protein parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure highly potent anti-PfCSP L9 complex with recombinant PfCSP. We found that Fab binds multivalently to CSP minor (NPNV) repeats, which stabilized by novel set affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations...
Abstract The symptoms of malaria occur during the blood stage infection, when parasite replicates within human red cells. parasite, Plasmodium vivax , selectively invades reticulocytes in a process which requires an interaction between ectodomain DARC receptor and Duffy-binding protein, PvDBP. Previous studies have revealed that small helical peptide from binds to region II PvDBP (PvDBP-RII). However, it is also known sulphation tyrosine residues on affects its binding these were not...
Abstract Malaria is a global health concern and research efforts are ongoing to develop superior vaccine RTS,S/AS01. To guide immunogen design, we seek comprehensive understanding of the protective humoral response against Plasmodium falciparum circumsporozoite protein (PfCSP). In contrast well-studied responses repeat region C-terminus, antibody N-terminal domain PfCSP (N-CSP) remains obscure. Here, characterized molecular recognition functional efficacy N-CSP-specific monoclonal 5D5. The...